Project Summary/Abstract One of the main stumbling blocks to using autonomic nerve modulation, as a therapy, is the inability to access peripheral branches of autonomic nerves innervating end organs in the abdominal and thoracic cavities. By placing electrodes on peripheral autonomic nerves, it will be possible to record and modulate these nerves and reproduce or inhibit various autonomic physiologic functions. In contrast to truncal vagal nerve stimulation, the effects of peripheral vagal nerve stimulation will be targeted at specific organs, and can be specific for particular physiologic effects. In addition, we hypothesize that the effects can be made more or less intense by varying the frequency, strength and/or duration of the nerve signal within a range that will not engender systemic side effects. Transmural endoscopy uses Z track tunneling through the esophagus and/or stomach to access the nerves and organs of the thoracic and abdominal cavity in a minimally-invasive manner. Using this minimally- invasive technique, safe and reliable access to the thoracic and abdominal cavity is easily obtained, and patients can go home on the same day after the procedure. The main objectives of the current study are to 1) develop a swine model, methods, technology, tools and devices to perform transmural endoscopy in order to identify, localize and place electrodes on the peripheral branches of the Vagus nerve, in order to record and stimulate the nerve near to the end organ and 2) to transition this technology for use in humans during POEM procedures. Nerve targets and end organs that can be reached through the esophagus are the lungs, heart, esophagus, small and great vessels of the thorax and stomach. Organs that can be reached through the stomach are the stomach, liver, pancreas, kidneys, small intestine, large and small vessels of the abdomen, spleen and colon. These techniques have the potential to treat many diseases that respond to stimulation of the autonomic nervous system. We are particularly optimistic about the future prospects of treating chronic hypertension, diabetes, GERD, gastroparesis, end stage CHF, end stage pulmonary disease such as pulmonary hypertension, and obesity to name a few of the obvious examples where peripheral autonomic nerve modification could have a significant impact on longevity and quality of life. We are excited to contribute to the development of next generation of neuromodulation devices and mapping of the PNS as a part of the SPARC program.